Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss

Abstract

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI;' KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the' KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium. Noise overexposure is a major cause of a variety of perceptual disabilities, including speech-in-noise difficulties, tinnitus, and hyperacusis. Here we show that exposure to noise levels that do not cause permanent threshold elevations or hair cell death can produce a loss of cochlear nerve synapses to inner hair cells as well as degeneration of medial olivocochlear (MOC) terminals contacting the outer hair cells. Enhancement of the MOC reflex can prevent both types of neuropathy, highlighting the potential use of drugs that increase α9α10 nicotinic cholinergic receptor activity as a pharmacotherapeutic strategy to avoid hidden hearing loss.

Strengthening of the efferent olivocochlear system leads to synaptic dysfunction and tonotopy disruption of a central auditory nucleus

“…1A). As recently shown (Boero et al, 2018), no abnormalities in peak I amplitude were observed in L9’T compared to WT mice at 8, 16 and 32 KHz either at P16 (Table 1) or P21 (Fig. 1B; Table 1).…”

Strengthening of the Efferent Olivocochlear System Leads to Synaptic Dysfunction and Tonotopy Disruption of a Central Auditory Nucleus

“…These might indicate differential effects in the maturation of different nuclei of the auditory pathway in mutant mice. As recently shown (Boero et al, 2018), no abnormalities in peak I amplitude were observed in L9ЈT compared with WT mice at 8, 16, and 32 kHz, either at P16 or P21 ( Fig. 2B; Table 1).…”

Synaptic Inhibition of Medial Olivocochlear Efferent Neurons by Neurons of the Medial Nucleus of the Trapezoid Body

“…The functions of medial olivocochlear (MOC) neurons are thought to inhibit cochlear activity via synapses onto cochlear outer hair cells (OHCs), and subsequently alter OHC electromotility and basilar membrane mechanics (Fex, 1967;Mountain, 1980;Siegel and Kim, 1982;Guinan, 1996Guinan, , 2010Elgoyhen and Katz, 2012). MOC neurons thereby exert a variety of downstream effects, including adjusting cochlear gain to respond to sound intensity spanning orders of magnitude (Galambos, 1956;Desmedt, 1962;Wiederhold and Peake, 1966;Wiederhold and Kiang, 1970;Geisler, 1974;Guinan and Gifford, 1988), improved hearing in background noise (Winslow and Sachs, 1987;Kawase et al, 1993), protection against noise-induced trauma (Rajan, 1988(Rajan, , 1995Reiter and Liberman, 1995;Taranda et al, 2009;Maison et al, 2013;Tong et al, 2013;Boero et al, 2018), and auditory attention (Oatman, 1976;Glenn and Oatman, 1977;Delano et al, 2007;Terreros et al, 2016). Disorders such as tinnitus and hyperacusis may alter the function of MOC neurons (Attias et al, 1996;Knudson et al, 2014).…”